Daniel P. Flaherty
Ph.D. - 2010 - University of Nebraska Medical Center (Mentor: Jonathan Vennerstrom)
Postdoc - 2010 - 2014 - University of Kansas, Specialized Chemistry Center (Mentor: Jeffrey Aube)
Twitter - @flahertylab
Lab Website - www.flahertylab.com
The Flaherty Lab pursues projects to validate novel therapeutic targets for the treatment of infectious disease, chronic pain, and cancer. At our core, we are a medicinal chemistry laboratory; however, in addition to organic synthesis and med chem optimization our lab also pursues assay development, high-throughput screening, biochemical/biophysical ligand-receptor analysis, structural characterization, and computational modeling. Trainees in the Flaherty lab acquire hands on experience in many of these areas to provide a holistic drug discovery training experience. We apply these approaches to the following projects that are currently in progress in the lab:
Inhibitors of Staphylococcus aureus RnpA
Ribonuclease P (RNAse P) is a ribozyme that has long been known to process pre-tRNA in bacteria species via cleavage of the 5' leader sequence. However, recent studies have shown that the protein subunit, RnpA, also has a role in mRNA degradation. Previous efforts to develop inhibitors for RnpA have focused on it's role in as a substrate binding domain in the ribozyme. We are tackling this problem from a different point of view and searching for molecules that are dual functional. Using both traditional and fragment-based screening approaches our lab is developing molecules that can inhibit one or both of these RNA metabolism processes as a means to validate targeting the RnpA subunit for small molecule drug discovery. This project is currently funded by the NIH through 2023 (R01AI134685)
Drug Repurposing for novel therapeutics against vancomycin-resistant Enterococcus (VRE) and Neisseria gonorrhoeae
Drug-repurposing is a method in which researchers use an FDA-approved drug for an indication that the drug was not originally approved for. Starting from a molecule that has already gained FDA-approval provides our team with hits that are already known to be safe and possess desirable drug-like pharmacokinetic and physicochemical properties. Starting from molecules with these known properties significantly shortens the time to the clinic. In our projects we have identified a class of FDA-approved drugs that inhibit both VRE and N. gonorrhoeae potently and selectively. The same class of molecules engage different targets in each pathogen. We are currently carrying out drug development for this class of inhibitors to combat VRE and N. gonorrhoeae infections in collaboration with Dr. Mohamed Seleem in the Purdue School for Veterinary Medicine. This project is currently funded by the NIH through 2024 (R01AI148523).
Modulators of UCHL1 activity
Deubiquitinating enzymes have become increasingly popular drug targets for a variety of indications. This class of enzyme is heavily involved in signaling pathways to turn on/off processes, control cellular trafficking, and sending proteins to degradation through the ubiquitin-proteasome system. Our lab is currently pursuing best-in-class inhibitors versus Ubiquitin C-terminal hydrolase L1 (UCHL1). UCHL1 expression correlates well with tumor size and invasiveness and further studies have shown that it appears to regulate pathways leading to metastasis. Our team is using a traditional and fragment-based approach to discover improved small molecule inhibitors with therapeutic potential to treating aggressive forms of cancer. We are also incorporating protein engineering methods to develop Ubiquitin variants that selectively bind to UCHL1 over all other DUBs. These variants will be leveraged for probing the DUB in cells.
Inhibitors of Adenylyl Cyclases
This project is a interdisciplinary collaboration involving four labs within MCMP. Dr. Watts lab has extensive expertise studying the pharmacology of adenylyl cyclases (AC) and has shown that AC1 is a potential target to treat inflammatory pain. This team has embarked upon as small molecule AC1 inhibitor campaign in which the Flaherty lab provides medicinal chemistry support and coordinates with the lab of Dr. Markus Lill for analog design based on computational models. Analogs to the Watts lab for testing and any prioritized molecules move to in vivo studies in Dr. Van Rijn's lab. This project embodies the benefits of housing both medicinal chemistry and pharmacology expertise in the same department. *Data image borrowed from Brust et al, Sci Signal, 2017, 10, eaah5381
Xufeng Cao (Post-Doctoral Research Associate)
Tiffany S. Dwyer (Graduate Student)
Chad Hewitt (Graduate Student)
Katrina J. Holly (Graduate Student)
Ryan D. Imhoff (Graduate Student)
Anil Kumar Marapaka (Post-Doctoral Research Associate)
Jason Andrew Scott (Graduate Student)
Molly S. Youse (Graduate Student)
Organic chemistry, structure-based drug design, molecular modeling, biochemical analysis, covalent inhibition
Service and Engagement
Member of the American Chemical Society, Organic and Medicinal Chemistry Divisions.
Review Editor for Frontiers in Molecular Biosciences
Grant Peer Reviewer:
- NIH CARBIRU Special Emphasis Panel (ad hoc), 2020
- NIH Drug Discovery for the Nervous System Study Section (ad hoc), 2020
- Indiana CTSI, 2019
- DoD CDMRP, 2019
- DoD PRMRP, 2019
MCMP 204 - Organic Chemistry I
NIAID R01AI134685 - Antibacterial inhibitors of RnpA
NIAID R01AI148523 - Repurposing novel selective drugs for treatment and decolonization of vancomycin resistant enterococcus
Administration and Committee Work
BSPS Oversight Committee
MCMP Graduate Admissions Committee
PULSe Program Graduate Admissions Committee
Publications from last 5 years -
Development of Ubiquitin Variants with Selectivity for Ubiquitin C-Terminal Hydrolase Deubiquitinases. Biochemistry. 2020 Sep 22;59(37):3447-3462. doi: 10.1021/acs.biochem.9b01076. Epub 2020 Sep 8. PubMed PMID: 32865982.
Optimization of 4-Substituted Benzenesulfonamide Scaffold To Reverse Acinetobacter baumannii Serum-Adaptive Efflux Associated Antibiotic Tolerance. ChemMedChem. 2020 Sep 16;15(18):1731-1740. doi: 10.1002/cmdc.202000328. Epub 2020 Aug 13. PubMed PMID: 32681604.
Optimization of Acetazolamide-Based Scaffold as Potent Inhibitors of Vancomycin-Resistant Enterococcus. J Med Chem. 2020 Sep 10;63(17):9540-9562. doi: 10.1021/acs.jmedchem.0c00734. Epub 2020 Aug 11. PubMed PMID: 32787141.
Congruent Release of Drug and Polymer from Amorphous Solid Dispersions: Insights into the Role of Drug-Polymer Hydrogen Bonding, Surface Crystallization, and Glass Transition. Mol Pharm. 2020 Apr 6;17(4):1261-1275. doi: 10.1021/acs.molpharmaceut.9b01272. Epub 2020 Mar 17. PubMed PMID: 32134677.
Biochemical and cellular characterization of a cyanopyrrolidine covalent Ubiquitin C-terminal hydrolase L1 inhibitor. Chembiochem.2019 Aug 26;. doi: 10.1002/cbic.201900434. [Epub ahead of print] PubMed PMID: 31449350.
Identification of Small Molecule Inhibitors of Staphylococcus aureus RnpA. Antibiotics (Basel). 2019 Apr 28;8(2). doi: 10.3390/antibiotics8020048. PubMed PMID: 31035380; PubMed Central PMCID: PMC6627331.
Optimization of a 1,3,4-oxadiazole series for inhibition of Ca2+/calmodulin-stimulated activity of adenylyl cyclases 1 and 8 for the treatment of chronic pain. Eur J Med Chem. 2019 Jan 15;162:568-585. doi: 10.1016/j.ejmech.2018.11.036. Epub 2018 Nov 16. PubMed PMID: 30472604; PubMed Central PMCID: PMC6310635.
Crystal structure of the ribonuclease-P-protein subunit from Staphylococcus aureus. Acta Crystallogr F Struct Biol Commun. 2018 Oct 1;74(Pt 10):632-637. doi: 10.1107/S2053230X18011512. Epub 2018 Sep 19. PubMed PMID: 30279314; PubMed Central PMCID: PMC6168776.
Optimization and Evaluation of Antiparasitic Benzamidobenzoic Acids as Inhibitors of Kinetoplastid Hexokinase 1.ChemMedChem. 2017 Dec 7;12(23):1994-2005. doi: 10.1002/cmdc.201700592. Epub 2017 Nov 16. PubMed PMID: 29105342; PubMed Central PMCID: PMC5808564.
Antiparasitic lethality of sulfonamidebenzamides in kinetoplastids. Bioorg Med Chem Lett. 2017 Feb 15;27(4):755-758. doi: 10.1016/j.bmcl.2017.01.043. Epub 2017 Jan 16. PubMed PMID: 28119024; PubMed Central PMCID: PMC5296257.
Lopez-Sambrooks, C; Shrimal, S.; Khodier, C.; Flaherty, D.P.; Charest, J.; Gao, N.; Lewis, T. A.; Lehrman, M. A.; Gilmore, R. Golden, J.; Contessa, J. N. Oligosaccharyltransferase inhibition induces senescence in RTK-driven tumor cells. Nat. Chem. Biol. 2016, 12, 1023 - 1030.